Despite a large body of evidence suggesting that altered synaptic mechanisms significantly contribute to the development of the epileptic focus, relatively little information is available. We believe that a promising model for studying synaptic changes is the kindling phenomenon, whereby repeated electrical (or chemical) stimulation of constant intensity progressively augments behavioral and electrophysiological responses. In preliminary studies of the rat hippocamus, we found that hippocamal pyramidial cells developed long-lasting supersensitivity to iontophoretically applied acetylcholine (ACH) following a kindling-induced afterdischarge (AD). This finding suggests that synaptic modulation may be fundamentally related to the increased neuronal excitability basic to kindling and the epileptic process. We propose to investigate the detailed relationship between the growth of the kindled AD and alterations in neuronal responsiveness to microiontophoretically applied (ACH) and other neurotransmitters (including glutamate, GABA, norepinephrine, dopamine and serotonin). Furthermore, we will investigate which synaptic pathways contribute to the growth of the hippocamal AD. At the end of our investigation, we would expect to understand the relative contributions of neurotransmitters and anatomic pathways to hippocamal epileptogenesis. We further expect that these studies will lead to new insights into how synaptic alterations might affect the kindling process and human epileptogenesis. A far ranging goal would be to use this information to develop strategies for therapeutic intervention in epileptogenesis, i.e., pre-convulsant therapy.